Long-term continual administration of doxepin in mice fed an HFD accelerated obesity development and aggravated hyperglycemia, glucose intolerance, Cr distribution changes, and renal impairment, all in parallel with decelerated metabolic homeostasis, increased fatty liver scores and Cr loss, and decreased skeletal muscle GLUT4 expression. This evidence concerns the gene SLC2A4 and obesity due to melanocortin 4 receptor deficiency.